Discovery of (4-Phenyl-cyclohexyl)acetate-Derived Tyrosylprotein Sulfotransferase 2 (TPST2) Inhibitors with Potent Anti-Tumor Activity for Immuno-Oncology Applications

Tyrosylprotein sulfotransferase 2 (TPST2) was recently
reported
to mediate the post-translational sulfation of interferon γ
(IFNγ) receptor, contributing to immunosuppression in tumor
microenvironment. Herein, we report the discovery of 77c with an IC50 value of 946 nM as a novel TPST2 inhibitor
through the structure–activity relationship (SAR) studies and
optimization of a hit compound, 44a, identified in the
enzyme-based screening of 6868 compounds from Korea Chemical Bank
(KCB) library. 77c was further evaluated for its binding
affinity at TPST2 and effects in IFNγ signaling in cell-based
functional assays. In silico docking analysis suggested
the putative binding site of 77c and key molecular interactions,
providing structural insights into TPST2 inhibition. Furthermore,
in the MC38 syngeneic tumor model, 77c significantly
suppressed tumor growth and synergized with anti-PD-1 therapy, leading
to enhanced T cell-mediated antitumor immunity characterized by increased
infiltration of effector CD8+ T cells and improved systemic
immune activation.